Abstract Parenteral nutrition-associated cholestasis (PNAC) is a significant complication of prolonged parenteral nutrition. An estimated 50,000 infants are at risk to develop PNAC each year in the United States. The disease is particularly common in premature infants and those who undergo major gastrointestinal operations in the neonatal period. PNAC is associated with a 50% risk of sepsis and a mortality rate as high as 20% to 30%. Studies have shown that soybean-based fat emulsions have a direct causative effect on the development of cholestasis and its progression to liver failure but this product remains the only FDA-approved intravenous lipid available in the United States. Given these two factors, several strategies have been undertaken to minimize the deleterious effects of soybean-based fat emulsions on the liver. One promising approach is the administration of a lower dose of the IV fat emulsion as both a treatment and preventative approach for PNAC. While IV fat emulsion dose reduction appears to offer substantial benefit in the treatment and prevention of PNAC in infants in small, retrospective evaluations, data from well-controlled clinical studies are not available. Several questions regarding IV fat emulsion dose reduction remain. Specifically, the timing of dose reduction and the optimal dose have not been elucidated. The overall long-term safety of these strategies in this population remain unknown particularly as they relate to neurodevelopmental outcomes. Limiting the dose of IV fat emulsion may have a negative effect on essential fatty acid levels which in turn may affect neurologic and behavioral development as essential fatty acids are crucial during brain development in the neonatal period. Little data exist regarding the long-term neurodevelopmental outcomes of neonates treated with IV fat emulsion dose reduction. This study will evaluate the hypothesis that a lower dose of IV fat emulsion will prevent and/or reduce the severity of PNAC when compared to a standard dose of IV fat emulsion without having negative effects on growth or neurodevelopmental outcomes. Study subjects will include surgical neonates who will be dependent on parenteral nutrition for a prolonged period of time. Subjects will be enrolled in a prospective, randomized multi-center trial comparing IV fat emulsion given at a standard (3 g/kg/day) or reduced (1 g/kg/day) dose. The primary outcome measure will be a comparison of the rate of rise of direct bilirubin between the two groups. Secondary outcome measures will include the time to development of PNAC as well as the incidence of essential fatty acid deficiency and/or poor growth in both study arms. Finally, neurodevelopmental outcomes will be assessed in all subjects at 12 and 24 months of age to assess the long- term safety of this treatment modality.